The central theme of this application is to demonstrate how IEX-1 deficiency protects mice against HFD diet-induced obesity and insulin resistance. By employing a reciprocal adaptive transfer technique to specifically delete IEX-1 from hematopoietically derived cells, we will elucidate a decisive role of IEX-1 in regulation of macrophages phenotype and inflammation during high calorie consumption. This maneuver will help us delineate if IEX-1 in hematopoietically derived cells is important for development of obesity or insulin resistance. Furthermore, IEX-1 is highly expressed in mitochondria where it regulates mitochondrial respiration by promoting degradation of mitochondrial F1F0-ATPase inhibitor IF1 protein. Therefore, we suspect that IEX- 1 may have a direct role in metabolism and energy homeostasis. We will assess glucose metabolism in individual tissues and energy expenditure in the absence of IEX-1 using hyperinsulinemic-euglycemic clamp and indirect calorimetry, respectively. Lastly, to gain a mechanistic insight into how IEX-1 deficiency prevents diet-induced switch in ATM phenotype, we will employ an in-vitro forced M1 polarization techniques in bone marrow-derived macrophages co-cultured in the absence or presence of primary adipocytes. The study will provide novel insights into a mechanistic linkage between IEX-1 and metabolic function, and obesity.